Acid ceramidase deficiency: Farber disease and SMA-PME

Abstract

Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.

Keywords: Ceramide; Lipid storage; Lipogranulomatosis; Lysosomal storage disorder; Lysosome; Metabolic disorder; Neuromuscular disease; SMA-PME; Sphingolipid; Sphingolipidosis; Spinal muscular atrophy.

Fig. 1

The typical clinical manifestations by organ type that have been reported in cases of Farber Disease (FD) and SMA-PME in the published literature. FD symptoms organized by neurological symptoms, ophthalmic symptoms, cardinal triad symptoms, respiratory symptoms, hematopoietic symptoms, gastrointestinal involvement, dermatological manifestations, liver disease, motor neuron and muscle weakness, and bone disease phenotypes

Fig. 2

Reaction schema of the hydrolysis of ceramide by acid ceramidase into sphingosine and free fatty acid

Fig. 3

Structure of the human ASAH1 gene with the protein and distribution of mutations. a ASAH1 genomic structure. b ASAH1 mature transcript structure. c Schematic of the ACDase protein with annotations for the signal peptide, α-subunit, and β-subunit. d Percentages of the reported 65 ASAH1 mutations by type for FD and SMA-PME. e Frequency of mutations by subunit and reported disease phenotype